Development of small-molecule probes that selectively kill cells induced to express mutant RAS
Open accessAbstract
Synthetic lethal screening is a chemical biology approach to identify small molecules that selectively kill oncogene-expressing cell lines with the goal of identifying pathways that provide specific targets against cancer cells. We performed a high-throughput screen of 303,282 compounds from the National Institutes of Health-Molecular Libraries Small Molecule Repository (NIH-MLSMR) against immortalized BJ fibroblasts expressing HRAS(G12V) followed by a counterscreen of lethal compounds in a series of isogenic cells lacking the HRAS(G12V) oncogene. This effort led to the identification of two novel molecular probes (PubChem CID 3689413, ML162 and CID 49766530, ML210) with nanomolar potencies and 4-23-fold selectivities, which can potentially be used for identifying oncogene-specific pathways and targets in cancer cells.
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Ten additional compounds from the erastin/RSL3 screen induce ferroptosis; all except DPI2 inhibited GPX4 directly, while DPI2 depleted GSH like erastin.
“The screening assay in which erastin and RSL3 were identified later revealed ten additional compounds that induce ferroptosis [24, 26]. All but one compound (DPI2) inhibited GPX4 directly, similar to RSL3. In contrast, DPI2 depleted GSH, like erastin [24].”
From Ferroptosis: Death by Lipid Peroxidation (2016) · cites this paper as [26]
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References 18 · Cited by 237
- Authors
- Weïwer, M., Bittker, J. A., Lewis, T. A., Shimada, K., Yang, W. S., MacPherson, L., Dandapani, S., Palmer, M., Stockwell, B. R., Schreiber, S. L., & Munoz, B.
- Affiliations
- Broad Institute (US)
- Howard Hughes Medical Institute (US)
- ORCID
- Venue
- Bioorganic & Medicinal Chemistry Letters
- Publisher
- Elsevier BV
- Published
- 2012-02
- Volume
- 22
- Issue
- 4
- Pages
- 1822-1826
- ISSN
- 0960-894X (ISSN-L)
- PMC
- PMC3528973
- OpenAlex
- W2010826470
- Cited by
- 237
- References
- 18
- Citations by year
- 2026: 16 · 2025: 31 · 2024: 28 · 2023: 33 · 2022: 32 · 2021: 19 · 2020: 24 · 2019: 19 · 2018: 9 · 2017: 5 · 2016: 8 · 2015: 6 · 2014: 4 · 2013: 2 · 2012: 1
- FWCI
- 0.91
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Bioorganic & Medicinal Chemistry Letters (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health
- National Institute of Mental Health (R03MH084117)
- National Human Genome Research Institute (1U54HG005032-1, U54HG005032)
- National Cancer Institute (R01CA097061, R01CA161061)
- National Institute of General Medical Sciences (R01GM085081)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
- Keywords
- synthetic lethality, HRAS, chemical probes, chemical genetic screen, counter-selection
- MeSH terms
- Animals, Cell Line, Drug Screening Assays, Antitumor, Fibroblasts, Humans, Mutation, Structure-Activity Relationship, Thiophenes, Molecular Structure, Proto-Oncogene Proteins p21(ras), Apoptosis, Inhibitory Concentration 50, Cell Line, Tumor, Rats, Small Molecule Libraries
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